EP0702672B1 - Substituted quinoline derivatives and their use as inhibitors of gastric acid secretion - Google Patents

Substituted quinoline derivatives and their use as inhibitors of gastric acid secretion Download PDF

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Publication number
EP0702672B1
EP0702672B1 EP94919046A EP94919046A EP0702672B1 EP 0702672 B1 EP0702672 B1 EP 0702672B1 EP 94919046 A EP94919046 A EP 94919046A EP 94919046 A EP94919046 A EP 94919046A EP 0702672 B1 EP0702672 B1 EP 0702672B1
Authority
EP
European Patent Office
Prior art keywords
compound
quinoline
mmol
butyryl
methylene chloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP94919046A
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German (de)
English (en)
French (fr)
Other versions
EP0702672A1 (en
Inventor
Carl Ingemar Starke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9302005A external-priority patent/SE9302005D0/xx
Priority claimed from SE9303970A external-priority patent/SE9303970D0/xx
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP0702672A1 publication Critical patent/EP0702672A1/en
Application granted granted Critical
Publication of EP0702672B1 publication Critical patent/EP0702672B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention relates to novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.
  • the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
  • Substituted quinoline derivatives that inhibit gastric acid secretion are known in the art, for example from EP-A-0 330 485, WO 92/12969, US-A-5 082 848, EP-A-0 259 174, US-A-5 143 920, EP-A-416 749 and WO 93/12090.
  • US-A-5 082 848, EP-A-0 259 174, US-A-5 143 920 and EP-A-416 749 disclose compounds which may undergo bioisosteric replacements to give compounds with the same activity on gastric acid secretion as compounds disclosed in EP-A-0 330 485.
  • WO 92/12969 and EP-A-0 330 485 disclose compounds with hydroxyalkoxy and alkoxyalkoxy in the 8-position.
  • compounds of the formula I which are 4-amino-3-acylquinoline derivatives in which the quinoline is substituted in the 8-position by alkylsulfinylethoxy, alkylsulfinylpropoxy, alkylsulfonylethoxy or alkylsulfonylpropoxy, are effective as inhibitors of gastric acid secretion, and that they exert this effect by inhibiting the gastrointestinal H + ,K + -ATPase.
  • the invention thus relates to compounds of the general formula I: or a pharmaceutically acceptable salt thereof, wherein
  • C 1 -C 6 alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • cycloalkyl denotes a cyclic alkyl group having a ring size from C 3 to C 6 , optionally additionally substituted by lower alkyl.
  • examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.
  • C 1 -C 6 alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • the end products of the formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
  • Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange.
  • the free base obtained may also form salts with organic or inorganic acids.
  • acids which form suitably therapeutically acceptable salts.
  • examples of such acids are hydrohalogen acids, sulfonic acids, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclc carboxyl or sulfonic adds, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
  • Preferred compounds of the formula I are those wherein
  • R 1 is CH 2 CH 2 CH 3 ; R 2 and R 3 is CH 3 ; R 4 is H; m is 2; and n is 1; i.e. the compound 3-butyryl-4-(2-methylphenylamino)-8-(2-methylsulfinylethoxy)quinoline.
  • the invention relates to compounds of the formula I for use in therapy.
  • the present invention also provides processes for the manufacture of the compounds with the general formula I. Such compounds are prepared in the following way:
  • This oxidation may be carried out by using an oxidizing agent such as sodium hypochlorite, nitric acid, hydrogen peroxide, (optionally in presence of vanadium compounds), peracids, peresters, ozone, dinitrogentetraoxide, jodosobensene, N-halosuccinimide, 1-chlorobensotriazole, t-butylhypochlorite, diazabicyclo-[2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfuryl chloride.
  • the oxidation takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers or ketones.
  • the oxidation may also be carded out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism.
  • the invention relates to the use of a compound as defined above for the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
  • the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrom.
  • the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration.
  • the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
  • the compounds of the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa.
  • active ingredients may be antimicrobial agents, especially:
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.
  • the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium steryl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium steryl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance.
  • Example 11 ( 1 H-NMR, 300 MHz, CDCl 3 ): 1.25 (m,6H), 2.73-2.81 (m,5H), 3.15 (q, 2H), 3.22 (m, 1H), 3.41-3.49 (m,1H), 4.62 (m,2H), 6.84 (d,1H), 6.93-7.19 (m,5H), 7.31 (d,1H), 9.19 (s,1H), 11.88 (s,1H).
  • Example 56 The filtrate from the first crystallization in Example 56 was evaporated.
  • the salt was neutralized with a saturated sodium bicarbonate solution in methylene chloride and water.
  • the organic layer was dried over sodium sulfate and the solvent was evaporated.
  • the solid residue (4.6 g, 0.011 mole) and L-(+)-tartaric acid (1.68 g, 0.011 mole) were dissolved in warm methanol (110 ml).
  • the solution was allowed to cool to room temperature and stirred for 72 h.
  • the precipitate was filtered off and washed with a total amount of 11 ml methanol giving 1.5 g of the tartaric salt. Recrystallization from methanol gave 1.05 g of the tartaric salt of Example 57.
  • the salt was neutralized with a saturated sodium bicarbonate solution in methylene chloride and water. The organic layer was dried over sodium sulfate and the solvent was evaporated. Trituration with isopropyl ether gave 0.7 g of the pure enantiomer.
  • a syrup containing 1% (weight per volume) of active substance is prepared from the following ingredients: Compound according to Example 2 1.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g Flavouring agent 0.05 g Ethanol 96% 5.0 g Distilled water q.s. to a final volume of 100 ml
  • Sugar and saccharine are dissolved in 60 g of warm water. After cooling the acid addition salt is dissolved in the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol are added. The mixture is diluted with water to a final volume of 100 ml.
  • the above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.
  • a tablet containing 50 mg of active compound is prepared from the following ingredients: Compound according to Example 2 500 g Lactose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked 50 g Magnesium stearate 15 g Sodium carbonate 6 g Distilled water q.s. Hydroxypropyl methylcellulose 36 g Polyethylene glycol 9 g Colour Titanium dioxide 4 g Purified water 313 g
  • a parenteral formulation for intravenous use containing 4 mg of active compound per ml, is prepared from the following ingredients: Compound according to Example 2 4 g Polyethylene glycol 400 for injection 400 g Disodium hydrogen phosphate q.s. Sterile water to a final volume of 1.000 ml
  • Compound according to Example 2 is dissolved in polyethylene glycol 400 and 550 ml of water is added. pH of the solution is brought to pH 7.4 by adding a water solution of disodium hydrogen phosphate and water is added to a final volume of 1000 ml. The solution is filtered through a 0.22 ⁇ m filter and immediately dispensed into 10 ml sterile ampoules. The ampoules are sealed.
  • mice Female rats of the Sprague-Dawly strain were used. They were equipped with cannulated fistulae in the stomach (lumen) and the upper part of the duodenum, for collection of gastric secretions and administration of test substances, respectively. A fourteen days recovery period after surgery was allowed before testing commenced.
  • the compounds 1-12 in Table 1 had an ED 50 value in the range of 1.0-12 ⁇ mole/kg. The results are based on gastric acid secretion during the second hour after drug/vehicle administration.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP94919046A 1993-06-11 1994-06-08 Substituted quinoline derivatives and their use as inhibitors of gastric acid secretion Expired - Lifetime EP0702672B1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE9302005A SE9302005D0 (sv) 1993-06-11 1993-06-11 New active compounds
SE9302005 1993-06-11
SE9303970 1993-11-30
SE9303970A SE9303970D0 (sv) 1993-11-30 1993-11-30 New active compounds
PCT/SE1994/000552 WO1994029274A1 (en) 1993-06-11 1994-06-08 New active compounds

Publications (2)

Publication Number Publication Date
EP0702672A1 EP0702672A1 (en) 1996-03-27
EP0702672B1 true EP0702672B1 (en) 2000-09-06

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP94919046A Expired - Lifetime EP0702672B1 (en) 1993-06-11 1994-06-08 Substituted quinoline derivatives and their use as inhibitors of gastric acid secretion

Country Status (25)

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US (1) US5889021A (ja)
EP (1) EP0702672B1 (ja)
JP (1) JP3623794B2 (ja)
CN (1) CN1045955C (ja)
AT (1) ATE196134T1 (ja)
AU (1) AU680516B2 (ja)
BR (1) BR9406772A (ja)
CA (1) CA2164875A1 (ja)
CZ (1) CZ326095A3 (ja)
DE (1) DE69425823T2 (ja)
EE (1) EE03123B1 (ja)
EG (1) EG20435A (ja)
ES (1) ES2150494T3 (ja)
FI (1) FI955896A (ja)
HU (1) HUT75122A (ja)
IL (1) IL109685A (ja)
IS (1) IS4164A (ja)
NO (1) NO305799B1 (ja)
NZ (1) NZ267740A (ja)
PL (1) PL177766B1 (ja)
RU (1) RU2142454C1 (ja)
SG (1) SG47820A1 (ja)
SK (1) SK154995A3 (ja)
TW (1) TW261613B (ja)
WO (1) WO1994029274A1 (ja)

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ES2877799T3 (es) * 2015-12-31 2021-11-17 Shanghai Pharmaceuticals Holding Co Ltd Sal de derivado de quinolina, formas polimórficas de la misma, métodos de preparación de la misma, composición y aplicaciones

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RU2142454C1 (ru) 1999-12-10
SG47820A1 (en) 1998-04-17
EG20435A (en) 1999-04-29
CN1125438A (zh) 1996-06-26
ES2150494T3 (es) 2000-12-01
DE69425823T2 (de) 2001-01-18
AU680516B2 (en) 1997-07-31
HU9503529D0 (en) 1996-02-28
ATE196134T1 (de) 2000-09-15
BR9406772A (pt) 1996-02-21
EE03123B1 (et) 1998-10-15
JP3623794B2 (ja) 2005-02-23
DE69425823D1 (de) 2000-10-12
NZ267740A (en) 1997-05-26
JPH09510951A (ja) 1997-11-04
FI955896A0 (fi) 1995-12-08
WO1994029274A1 (en) 1994-12-22
US5889021A (en) 1999-03-30
CZ326095A3 (en) 1996-05-15
AU7012194A (en) 1995-01-03
SK154995A3 (en) 1996-09-04
EP0702672A1 (en) 1996-03-27
FI955896A (fi) 1995-12-08
CN1045955C (zh) 1999-10-27
NO305799B1 (no) 1999-07-26
CA2164875A1 (en) 1994-12-22
PL177766B1 (pl) 2000-01-31
HUT75122A (en) 1997-04-28
IL109685A0 (en) 1994-11-28
IL109685A (en) 1999-03-12
NO954928D0 (no) 1995-12-05
IS4164A (is) 1994-12-12
PL311957A1 (en) 1996-03-18
TW261613B (ja) 1995-11-01
NO954928L (no) 1995-12-05

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